-
Biochimica Et Biophysica Acta Dec 2013Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of... (Review)
Review
Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer's disease. Upon assembly with its three protein cofactors (nicastrin, Aph-1 and Pen-2), presenilin undergoes autoproteolysis into two subunits, each of which contributes one of the catalytic aspartates to the active site. A family of presenilin homologs, including signal peptide peptidase, possess proteolytic activity without the need for other protein factors, and these simpler intramembrane aspartyl proteases have given insight into the action of presenilin within the γ-secretase complex. Cellular and molecular studies support a nine-transmembrane topology for presenilins and their homologs, and small-molecule inhibitors and cysteine scanning with crosslinking have suggested certain presenilin residues and regions that contribute to substrate recognition and handling. Identification of partial complexes has also offered clues to protein-protein interactions within the γ-secretase complex. Biophysical methods have allowed 3D views of the γ-secretase complex and presenilins. Most recently, the crystal structure of a microbial presenilin homolog has confirmed a nine-transmembrane topology and intramembranous location and proximity of the two conserved and essential aspartates. The crystal structure also provides a platform for the formulation of specific hypotheses regarding substrate interaction and catalysis as well as the pathogenic mechanism of Alzheimer-causing presenilin mutations. This article is part of a Special Issue entitled: Intramembrane Proteases.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Coenzymes; Crystallography, X-Ray; Endopeptidases; Humans; Membrane Glycoproteins; Membrane Proteins; Models, Molecular; Peptide Hydrolases; Presenilin-1; Presenilin-2; Protein Binding; Protein Structure, Tertiary; Proteolysis; Signal Transduction; Substrate Specificity
PubMed: 24099007
DOI: 10.1016/j.bbamem.2013.04.015 -
Journal of Alzheimer's Disease : JAD Apr 2016Research into Alzheimer's disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase... (Review)
Review
Research into Alzheimer's disease pathology and treatment has often focused on presenilin proteins. These proteins provide the key catalytic activity of the γ-secretase complex in the cleavage of amyloid-β precursor protein and resultant amyloid tangle deposition. Over the last 25 years, screening novel drugs to control this aberrant proteolytic activity has yet to identify effective treatments for the disease. In the search for other mechanisms of presenilin pathology, several studies have demonstrated that mammalian presenilin proteins also act in a non-proteolytic role as a scaffold to co-localize key signaling proteins. This role is likely to represent an ancestral presenilin function, as it has been described in genetically distant species including non-mammalian animals, plants, and a simple eukaryotic amoeba Dictyostelium that diverged from the human lineage over a billion years ago. Here, we review the non-catalytic scaffold role of presenilin, from mammalian models to other biomedical models, and include recent insights using Dictyostelium, to suggest that this role may provide an early evolutionary function of presenilin proteins.
Topics: Animals; Biological Evolution; Dictyostelium; Mammals; Matrix Attachment Regions; Mice; Presenilins; Signal Transduction
PubMed: 27079701
DOI: 10.3233/JAD-150940 -
Annals of Neurology May 2004
Review
Topics: Animals; Dementia; Humans; Membrane Proteins; Mutation; Presenilin-1; Presenilin-2
PubMed: 15122699
DOI: 10.1002/ana.20103 -
Cold Spring Harbor Perspectives in... Dec 2017The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other... (Review)
Review
The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch. Here, we detail the structural and chemical biology of this unusual enzyme. Taken together, these studies suggest that the complex exists in several conformations, and subtle long-range (allosteric) shifts in the conformation of the complex underpin substrate access to the catalytic site and the mechanism of action for allosteric inhibitors and modulators. Understanding the mechanics of these shifts will facilitate the design of γ-secretase modulator (GSM) compounds that modulate the relative efficiency of γ, ɛ, ζ site cleavage and/or substrate specificity.
Topics: Amyloid beta-Protein Precursor; Animals; Humans; Presenilin-1; Presenilin-2
PubMed: 28320827
DOI: 10.1101/cshperspect.a024067 -
International Journal of Molecular... Jan 2020Alzheimer's disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations... (Review)
Review
Alzheimer's disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes. AD mutations contribute to the generation of toxic amyloid β (Aβ) peptides and the formation of cerebral plaques, leading to the formulation of the amyloid cascade hypothesis for AD pathogenesis. Many drugs have been developed to inhibit this pathway but all these approaches currently failed, raising the need to find additional pathogenic mechanisms. Alterations in cellular calcium (Ca) signaling have also been reported as causative of neurodegeneration. Interestingly, Aβ peptides, mutated presenilin-1 (PS1), and presenilin-2 (PS2) variously lead to modifications in Ca homeostasis. In this contribution, we focus on PS2, summarizing how AD-linked PS2 mutants alter multiple Ca pathways and the functional consequences of this Ca dysregulation in AD pathogenesis.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Calcium Signaling; Humans; Presenilin-1; Presenilin-2
PubMed: 31991578
DOI: 10.3390/ijms21030770 -
Annals of the New York Academy of... 2000Familial Alzheimer's disease (FAD) is now linked to at least three genes encoding the amyloid precursor protein (APP) on chromosome 21, and presenilin 1 and 2 on... (Review)
Review
Familial Alzheimer's disease (FAD) is now linked to at least three genes encoding the amyloid precursor protein (APP) on chromosome 21, and presenilin 1 and 2 on chromosome 14 and 1, respectively. FAD cases in whom presenilin mutations occur are more frequent than those with APP mutations. However, altogether they only account for approximately 0.1% of all the people suffering from Alzheimer's disease (AD), and the causes of the remaining 99.9% of the sporadic form of AD or senile dementia remain unknown. Since FAD presents with the same neuropathological features as sporadic AD, i.e., cognitive impairments and the amyloid plaques and tangles in the brain, our working hypothesis is that similar molecular pathogenic mechanisms underly both sporadic and familial AD. It follows that APP and the presenilins must be key players in the disease. Detailed knowledge about the cell biology of these proteins will be a rich source of insight into the pathology of AD, but will also shed light on the fundamental neurobiology of these proteins.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 21; Humans; Membrane Proteins; Mutation; Presenilin-1; Presenilin-2
PubMed: 11193144
DOI: 10.1111/j.1749-6632.2000.tb06917.x -
Journal of Alzheimer's Disease : JAD 2011The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated... (Review)
Review
The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/γ-secretase-mediated cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex. We begin by discussing the steps of AβPP processing and PS/γ-secretase complex composition and localization, which give clues to how and where the processing of other PS/γ-secretase substrates may take place. Then we summarize the typical features of PS/γ-secretase-mediated protein processing. Finally, we recapitulate the current knowledge on the possible physiological function of PS/γ-secretase-mediated cleavage of specific substrate proteins.
Topics: Amyloid Precursor Protein Secretases; Animals; Humans; Presenilins; Substrate Specificity
PubMed: 21335653
DOI: 10.3233/JAD-2011-101065 -
Journal of Neurochemistry May 2005Alzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by the accumulation of beta-amyloid (Abeta) plaques and neurofibrillary... (Review)
Review
Alzheimer's disease (AD) is the most common form of dementia and is characterized pathologically by the accumulation of beta-amyloid (Abeta) plaques and neurofibrillary tangles in the brain. Genetic studies of AD first highlighted the importance of the presenilins (PS). Subsequent functional studies have demonstrated that PS form the catalytic subunit of the gamma-secretase complex that produces the Abeta peptide, confirming the central role of PS in AD biology. Here, we review the studies that have characterized PS function in the gamma-secretase complex in Caenorhabditis elegans, mice and in in vitro cell culture systems, including studies of PS structure, PS interactions with substrates and other gamma-secretase complex members, and the evidence supporting the hypothesis that PS are aspartyl proteases that are active in intramembranous proteolysis. A thorough knowledge of the mechanism of PS cleavage in the context of the gamma-secretase complex will further our understanding of the molecular mechanisms that cause AD, and may allow the development of therapeutics that can alter Abeta production and modify the risk for AD.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Aspartic Acid Endopeptidases; Endopeptidases; Humans; Membrane Proteins; Models, Biological; Presenilin-1; Presenilin-2; Receptors, Notch; Sequence Alignment; Structure-Activity Relationship
PubMed: 15857382
DOI: 10.1111/j.1471-4159.2005.03099.x -
Cell Oct 2007The presenilin-containing gamma-secretase complex is an unusual membrane-embedded protease that processes a wide variety of integral membrane proteins, clearing protein... (Review)
Review
The presenilin-containing gamma-secretase complex is an unusual membrane-embedded protease that processes a wide variety of integral membrane proteins, clearing protein stubs from the lipid bilayer and participating in critical signaling pathways. The protease is also central to Alzheimer's disease and certain cancers and is therefore an important therapeutic target. Here we highlight recent progress in deciphering the role of presenilin/gamma-secretase in biology and medicine and pose key questions for future study.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Humans; Presenilin-1; Presenilin-2; Protein Conformation; Signal Transduction
PubMed: 17956719
DOI: 10.1016/j.cell.2007.10.012 -
Nature Communications Oct 2022Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for...
Inhibition of γ-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of γ-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing γ-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 Å. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting γ-secretase.
Topics: Presenilin-1; Amyloid Precursor Protein Secretases; Presenilin-2; Cryoelectron Microscopy; Protein Isoforms
PubMed: 36272978
DOI: 10.1038/s41467-022-33817-5